Veterinarian composition comprising an organic salt of levamisole in combination with at least one avermectine and/or milbemycine

ABSTRACT

Veterinarian composition comprising an organic salt of levamisole in combination with at least one avermectine and/or milbemycine. A veterinarian formulation comprising of organics salts of levamisole, more specifically to the disophenolat salt of levamisole and the nitroxynil-salt of levamisole with avermectines and milbemycines and its use in treatment of helminthiasis in mammals, in particular in bovines, swines, caprines, equines, ovines, canines and felines.

STATEMENT OF RELATED APPLICATIONS

This patent application is the United States PCT Chapter II National Phase of PCT/BR2006/000282, having an International Filing Date of 18 Dec. 2006, which claims priority on Brazilian Patent Application No. PI 0506279-9, having a filing date of 16 Dec. 2005, both of which are incorporated herein by this reference in their entireties.

BACKGROUND OF THE INVENTION

The association of different classes of substances presenting antihelminthic actions aims to combat an increasing resistance of parasites to most of the drugs used. The resistance of parasites to different classes of antihelminthic drugs has been reported since early use of these drugs. The resistance for benzimidazole is all over the world. Studies have been reported, mainly related to three main species of bovine's parasites: Ostertagia, Trichostrongylus, Cooperia. Although parasites resistance to levamisole is well known, it is much more restrict than to benzimidazoles. Resistance and crossed resistance reports have been reported, mainly to Cooperia species.

The strategy to combat this resistance has been trying to avoid the indiscriminate use of antihelminthic drugs, to alternate drugs during treatment and to use potential number of parasites which survive the treatment. The association of active principles aiming a synergetic function among them is a well known strategy, mainly in the treatment of pathogenic agents with bacteria, protozoans, fungus, and parasites. A real synergism occurs when the association of two or more pharmaceutical actives is higher than all individual actions together.

The aim of this invention is to describe the use of organic salts of levamisole associated to avermectines and/or milbemycines in the combat to helminthiasis.

Levamisole (L-2,3,5,6-tetrahydro-6-phenil-imidazo-[2,1,b thiazole), it is an antiparasitary widely used for intestinal control of nematodes and respiratory worms in some animals. Due to its basic characteristic, it forms salts with organic and inorganic acids, depending on pk_(a) of this acid.

Antiparasitaries such as disophenol (2,6-dilodo-4-nitrofenol) and nitroxinil (xxx), which are used to control trematodes and some nematodes, produce a salt with levamisole under some conditions due to its acid characteristic of phenol group of these molecules. The description, obtainment, and use of nitroxynil-salt of levamisole were described in the patent GB 2150024 A. Disophenol of levamisole and nitroxynil-salt of levamisole from now will be referred only as levamisole organic salts, when suitable.

Avermectines, a compound which belongs to macrocyclic lactones, are powerful antiparasitary agents which are used to combat parasites in mammals. They are secondary metabolic produced by Streptomyces avemitilis, obtained through a fermenting process. Some avermectines are obtained in a semi synthetic composition as ivermectin, which is obtained through abamectine hydrogenization. A series of compounds denominated avermectines are abamectine, doramectine, eprinomectine, ivermectin and selamectine.

Milbemycine is similar to avermectines in their structure, because they have a 16 membered ring structures. However, it does not have a disaccharidic sub unit and there are constituent differences. Milbemycine used in the association are selected from the group consisting of moxidectine, milbemycine and milbemycine oxima.

Considering these aspects, it is known that levamisole disophenolat, as well as levamisole nitroxynil-salt, both combine the action of levamisole against nematodes, for example, Haemonchus contortus, Ostertagia spp., Trichostrongylus spp. (example: Trichostrongylus axei), Cooperia spp. (Cooperia oncophora), Nematordirus spp. (example: Oesaphagostomum venulosum), Strongyloides spp. (example: Strongyloides papillosus), Bunostomum spp. (ex: Bunostomum trigonocephalum), Chabertia spp (ex: Chabertia ovina), Trichuris spp. (ex: Trichuris ovis) and Dictyocaulus spp. (ex: Dictyocaulus filaria and Dictyocaulus viviparous) with the action of disofenol or nitroxinil against trematodes, for example, Fasciola hepatic and gigantic Fasciola, and some nematodes, for example, Haemonchus contortus, Bunostomum spp. Oesaphagostomum spp., Parafilaria bovicola. Considering that levamisole presents a low action against Ostertagia parasites and a good action against Cooperia class, and avermectines and milbemycine has a good inverse action, which means low action against Cooperia and good action against Ostertagia, a combination of actions of levamisole disophenolat and levamisole nitroxynil-salt with avermectines and milbemycines, aiming an wide spectrum formulation against parasites, besides a synergism of actions among actives. In such case, this association maybe indicated as a parasiticide in the treatment of nematodes, cestodes, and trematodes in bovines, swine, caprines, equines, ovines, canines and felines.

Associations of avermectines and levamisole have already been described before, in patent WO 00061068 and in patent application WO 2004/009080 A1. The greatest discovery in the study is the use of salts of levamisole, which besides levamisole action they present fascioliscide action, when associated with avermectines. Other associations with fascioliscide compounds were proposed in documents WO 95/05812 and GB 2386067A, both describing the association of avermectines and milbemycines with closantel.

BRIEF SUMMARY OF THE INVENTION

This invention aims a veterinarian pharmaceutical formulation which presents fascioliscide action and a potent action against nematodes, cestodes, trematodes. Other aim of the invention is to describe a new veterinarian pharmaceutical product presenting the association of organic salts of levamisole with avermectines and milbemycines. This invention also aims to describe the association of disophenolat of levamisole with avermectines and milbemycines for antiparasitary agent.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention presents new veterinarian products from the association of avermectines and milbemycines with other antiparasitary agents, such as organic salts of levamisole.

Levamisole organic salts used in this invention are of levamisole nitroxynil-salt and levamisole disophenolat.

Avermectines and milbemycines used in this invention are abamectine, ivermectin, doramectine, eprinomectine, selamectine, moxidectine, milbemycine and milbemycine oxima.

The used dosage will depend on the helminthes' nature, the animal which will be treated and administration route. Nitroxynil-salt of levamisole can range from 1 to 50 mg of nitroxynil-salt of levamisole per weigh/kilo, rather from 5 to 15 mg of nitroxynil-salt of levamisole per body weight, considering that dosage of 7.2 mg/kg of weight brings satisfactory results in the control of parasites. Disophenolat of levamisole can range from 1 to 50 mg of levamisole nitroxynil-salt per kilo of body weigh, considering that a dosage of 8.9 mg/kg of weight generally brings satisfactory results in the control of parasites. Avermectines and milbemycines dosages range from 5 a 500 ug of the active per kilo of weight, rather from 50 to 350 ug of the active per kilo of body weight, but a dosage of 200 ug/kilo of weight generally has satisfactory results in the control of parasites.

The pharmaceutical formulations, according to this invention, can be used to administrate the associations of levamisole organic salts with milbemycines and/or avermectines in order to kill internal parasites, such as, nematodes, cestodes, trematodes and fasciola, parasites in animals such as bovines, swines, caprines, felines, canines, equines; according to the dosages and purposes presented in this study specifically for these associations.

The administration could be parentheral, which means, intravenous, subcutaneous or intra muscular administration; oral administration as a solution or suspension, in pills, bolus, capsules or as food supplement; can be administrated by derm through transdermic formulations type “pour on”. The administration is done with a unique and effective dose, and administration route is rather parentheral.

The associations are rather done among levamisole organic salt and avermectines or milbemycines. For example, the association of levamisole nitroxynil-salt with abamectine in a parentheral veterinarian formulation. These can be free associations with the use of one or more levamisole organic salts and one or more avermectines or milbemycines, or the mix of them.

It is important to understand that the invention is not limited to details and steps here described. It is possible to be done or performed in different ways, and clarifying that the used terminology aims the description and not the limitation thereof. 

1. A veterinarian composition comprising an organic salt of levamisole in combination with avermectines and/or milbemycines.
 2. The veterinarian composition according to claim 1, wherein said levamisole organic salt comprises levamisole disophenolat.
 3. The veterinarian composition according to claim 1, wherein said levamisole organic salt comprises levamisole nitroxynil-salt.
 4. The veterinarian composition according to claim 1, wherein said avermectines and milbemycines are selected from the group consisting of abamectine, ivermectin, doramectine, eprinomectine, selamectine, moxidectine, milbemycine and milbemycine oxima.
 5. The veterinarian composition according to claim 1, wherein the composition comprises disophenolat of levamisole in association with avermectines and/or milbemycines in dosages ranging from 20-80% in weight of disophenolat of levamisole.
 6. The veterinarian composition according to claim 1, wherein the composition comprises nitroxynil-salt of levamisole in association with avermectines and/or milbemycines in dosages ranging from 20-80% in weight of nitroxynil-salt of levamisole.
 7. The veterinarian composition according to claim 1, wherein the composition comprises avermectines selected from the group consisting of abamectine, ivermectin, doramectine, eprinomectine, selamectine, and moxidectine in association with disophenolat of levamisole and nitroxynil-salt of levamisole in dosages ranging from 0.5-15% in weight of active. 